Yuliya S. Nikolova

Multilocus Genetic Profile for Dopamine Signaling Predicts Ventral Striatum Reactivity

Research integrating neuroimaging and molecular genetics has yielded important insights into how variability in brain chemistry predicts individual differences in brain function, behavior and related risk for psychopathology. However, existing studies have been limited by their focus on the independent effects of single polymorphisms with modest impact on brain chemistry. Here, we explored the effects of five functional polymorphisms affecting dopamine (DA) signaling on reward-related ventral striatum (VS) reactivity, measured with BOLD fMRI, in a sample of 69 Caucasians. We also compiled individual multilocus genetic profile scores reflecting the additive effects of alleles conferring relatively increased DA signaling across the five polymorphic loci: DAT1 9-repeat, DRD4 7-repeat, DRD2 -141C Del, DRD2 Taq1A C (A2), and COMT 158Met. These multilocus DA profile scores accounted for 10.9% of the inter-individual variability in reward-related VS reactivity. In contrast, none of the individual polymorphisms accounted for significant variability. Our results show that biologically informed multilocus genetic profiles have unique promise as indices of variability in brain chemistry that may yield advances in mapping individual differences in behaviorally relevant brain function. In turn, such genetic profiles may fuel gene–environment interactions research establishing trajectories of risk for psychopathology.

Beyond genotype: serotonin transporter epigenetic modification predicts human brain function

We examined epigenetic regulation in regards to behaviorally and clinically relevant human brain function. Specifically, we found that increased promoter methylation of the serotonin transporter gene predicted increased threat-related amygdala reactivity and decreased mRNA expression in postmortem amygdala tissue. These patterns were independent of functional genetic variation in the same region. Furthermore, the association with amygdala reactivity was replicated in a second cohort and was robust to both sampling methods and age.

Ventral striatum reactivity to reward and recent life stress interact to predict positive affect.

BACKGROUND Stressful life events are among the most reliable precipitants of major depressive disorder; yet, not everyone exposed to stress develops depression. It has been hypothesized that robust neural reactivity to reward and associated stable levels of positive affect (PA) may protect against major depressive disorder in the context of environmental adversity. However, little empirical data exist to confirm this postulation. Here, we test the hypothesis that individuals with relatively low ventral striatum (VS) reactivity to reward will show low PA levels in the context of recent life stress, while those with relatively high VS reactivity will be protected against these potentially depressogenic effects. METHODS Differential VS reactivity to positive feedback was assessed using blood oxygen level-dependent functional magnetic resonance imaging in a sample of 200 nonpatient young adults. Recent life stress, current depressive symptoms, and PA were assessed via self-report. Linear regression models were used to investigate the moderating effects of VS reactivity on the relationship between recent stress and state PA across participants. RESULTS Recent life stress interacted with VS reactivity to predict self-reported state PA, such that higher levels of life stress were associated with lower PA for participants with relatively low, but not for those with high, VS reactivity. These effects were independent of age, gender, race/ethnicity, trait PA, and early childhood trauma. CONCLUSIONS The current results provide empirical evidence for the potentially protective role of robust reward-related neural responsiveness against reductions in PA that may occur in the wake of life stress and possibly vulnerability to depression precipitated by stressful life events.

Neurogenetics of Depression: A Focus on Reward Processing and Stress Sensitivity

Major depressive disorder (MDD) is etiologically complex and has a heterogeneous presentation. This heterogeneity hinders the ability of molecular genetic research to reliably detect the small effects conferred by common genetic variation. As a result, significant research efforts have been directed at investigating more homogenous intermediate phenotypes believed to be more proximal to gene function and lie between genes and/or environmental effects and disease processes. In the current review we survey and integrate research on two promising intermediate phenotypes linked to depression: reward processing and stress sensitivity. A synthesis of this burgeoning literature indicates that a molecular genetic approach focused on intermediate phenotypes holds significant promise to fundamentally improve our understanding of the pathophysiology and etiology of depression, which will be required for improved diagnostic definitions and the development of novel and more efficacious treatment and prevention strategies. We conclude by highlighting challenges facing intermediate phenotype research and future development that will be required to propel this pivotal research into new directions.

Can we observe epigenetic effects on human brain function

Imaging genetics has identified many contributions of DNA sequence variation to individual differences in brain function, behavior, and risk for psychopathology. Recent studies have extended this work beyond the genome by mapping epigenetic differences, specifically gene methylation in peripherally assessed DNA, onto variability in behaviorally and clinically relevant brain function. These data have generated understandable enthusiasm for the potential of such research to illuminate biological mechanisms of risk. We use our research on the effects of genetic and epigenetic variation in the human serotonin transporter on brain function to generate a guardedly optimistic opinion that the available data encourage continued research in this direction, and suggest strategies to promote faster progress.

Divergent responses of the amygdala and ventral striatum predict stress-related problem drinking in young adults: possible differential markers of affective and impulsive pathways of risk for alcohol use disorder.

Prior work suggests that there may be two distinct pathways of alcohol use disorder (AUD) risk: one associated with positive emotion enhancement and behavioral impulsivity, and another associated with negative emotion relief and coping. We sought to map these two pathways onto individual differences in neural reward and threat processing assessed using blood-oxygen-level-dependent functional magnetic resonance imaging in a sample of 759 undergraduate students (426 women, mean age 19.65±1.24 years) participating in the Duke Neurogenetics Study. We demonstrate that problem drinking is highest in the context of stress and in those with one of two distinct neural phenotypes: (1) a combination of relatively low reward-related activity of the ventral striatum (VS) and high threat-related reactivity of the amygdala; or (2) a combination of relatively high VS activity and low amygdala reactivity. In addition, we demonstrate that the relationship between stress and problem alcohol use is mediated by impulsivity, as reflected in monetary delay discounting rates, for those with high VS–low amygdala reactivity, and by anxious/depressive symptomatology for those with the opposite neural risk phenotype. Across both neural phenotypes, we found that greater divergence between VS and amygdala reactivity predicted greater risk for problem drinking. Finally, for those individuals with the low VS–high amygdala risk phenotype we found that stress not only predicted the presence of AUD diagnosis at the time of neuroimaging but also subsequent problem drinking reported 3 months following study completion. These results offer new insight into the neural basis of AUD risk and suggest novel biological targets for early individualized treatment or prevention.

Stress-related anhedonia is associated with ventral striatum reactivity to reward and transdiagnostic psychiatric symptomatology.

BACKGROUND Early life stress (ELS) is consistently associated with increased risk for subsequent psychopathology. Individual differences in neural response to reward may confer vulnerability to stress-related psychopathology. Using data from the ongoing Duke Neurogenetics Study, the present study examined whether reward-related ventral striatum (VS) reactivity moderates the relationship between retrospectively reported ELS and anhedonic symptomatology. We further assessed whether individual differences in reward-related VS reactivity were associated with other depressive symptoms and problematic alcohol use via stress-related anhedonic symptoms and substance use-associated coping. METHOD Blood oxygen level-dependent functional magnetic resonance imaging (fMRI) was collected while participants (n = 906) completed a card-guessing task, which robustly elicits VS reactivity. ELS, anhedonic symptoms, other depressive symptoms, coping behavior, and alcohol use behavior were assessed with self-report questionnaires. Linear regressions were run to examine whether VS reactivity moderated the relationship between ELS and anhedonic symptoms. Structural equation models examined whether this moderation was indirectly associated with other depression symptoms and problematic alcohol use through its association with anhedonia. RESULTS Analyses of data from 820 participants passing quality control procedures revealed that the VS × ELS interaction was associated with anhedonic symptoms (p = 0.011). Moreover, structural equation models indirectly linked this interaction to non-anhedonic depression symptoms and problematic alcohol use through anhedonic symptoms and substance-related coping. CONCLUSIONS These findings suggest that reduced VS reactivity to reward is associated with increased risk for anhedonia in individuals exposed to ELS. Such stress-related anhedonia is further associated with other depressive symptoms and problematic alcohol use through substance-related coping.

Neural responses to threat and reward interact to predict stress-related problem drinking: A novel protective role of the amygdala

BackgroundResearch into neural mechanisms of drug abuse risk has focused on the role of dysfunction in neural circuits for reward. In contrast, few studies have examined the role of dysfunction in neural circuits of threat in mediating drug abuse risk. Although typically regarded as a risk factor for mood and anxiety disorders, threat-related amygdala reactivity may serve as a protective factor against substance use disorders, particularly in individuals with exaggerated responsiveness to reward.FindingsWe used well-established neuroimaging paradigms to probe threat-related amygdala and reward-related ventral striatum reactivity in a sample of 200 young adult students from the ongoing Duke Neurogenetics Study. Recent life stress and problem drinking were assessed using self-report. We found a significant three-way interaction between threat-related amygdala reactivity, reward-related ventral striatum reactivity, and recent stress, wherein individuals with higher reward-related ventral striatum reactivity exhibit higher levels of problem drinking in the context of stress, but only if they also have lower threat-related amygdala reactivity. This three-way interaction predicted both contemporaneous problem drinking and problem drinking reported three-months later in a subset of participants.ConclusionsThese findings suggest complex interactions between stress and neural responsiveness to both threat and reward mediate problem drinking. Furthermore, they highlight a novel protective role for threat-related amygdala reactivity against drug use in individuals with high neural reactivity to reward.

Perception of a Naturalistic Stressor Interacts with 5-HTTLPR/rs25531 Genotype and Gender to Impact Reward Responsiveness

Background: Stressful life experiences frequently precede the onset of major depression; however, the mechanisms that underlie this link are poorly understood. Importantly, some individuals are more susceptible to the depressogenic effects of stress than others. Carriers of the S or LG allele of the 5-HTTLPR/rs25531 polymorphisms (S’ participants) have been found to be more prone to developing depression under stress relative to L or LA homozygotes (L’ participants). Moreover, emerging evidence indicates that stress-induced anhedonia may be a mechanism underlying links between stress and depression. Given these findings, we hypothesized that exposure to a naturalistic stressor (school final examinations) would disrupt reward responsiveness (a key behavioral component of anhedonia), and that this effect would be strongest in S’ participants. Methods: To objectively assess reward responsiveness, we administered a probabilistic reward task to 70 Bulgarian high school students over two sessions in the 6-month period preceding school finals. For each participant, the two sessions were designated as the ‘stress’ and ‘control’ conditions based on self-reported perceived stress. Results: A genotype × condition interaction emerged in males, with S’ participants showing larger stress-related reduction in reward responsiveness relative to L’ participants. Conclusion: While in need of replication in a larger sample, our results indicate that stress associated with a real-life event is linked to reduced reward responsiveness, the susceptibility to which is modulated by 5-HTTLPR/rs25531 genotype. Although preliminary, these findings identify anhedonia as a promising mechanism linking 5-HTTLPR/rs25531 genotype and stress to depression.

Functional genetic variants in the vesicular monoamine transporter 1 modulate emotion processing

Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular monoamine transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology.